James Sanderson

The development of a palladacyclic precatalyst supported by a new biaryl(dialkyl)phosphine ligand (VPhos) in combination with octanoic acid/sodium octanoate as a simple and effective surfactant system provided an improved catalyst system for the rapid construction of a broad spectrum of alkylated scaffolds from alkyl zinc reagents generated in situ.

Happy to get its feet wet: VPhos was developed as a hybrid ligand incorporating structural elements of existing ligands for improved activity in the micelle-enhanced palladium-catalyzed cross-coupling of non-aromatic O- and N-heterocyclic alkyl bromides with (hetero)aryl halides (see scheme). The Pd/VPhos catalyst (5 mol %) and a simple surfactant system based on octanoic acid enabled the efficient synthesis of a broad range of alkylated (hetero)arenes.

Amine Alkylation In their Communication on page 15046 ff., R. Kempe et al. describe the alkylation of amines by alcohols in the presence of a Co catalyst under mild conditions. Selectively monoalkylated aromatic amines as well as unsymmetrically substituted diamines are obtained.

For a while, the reactivity of gold complexes was largely dominated by their Lewis acid behavior. In contrast to the other transition metals, the elementary steps of organometallic chemistry—oxidative addition, reductive elimination, transmetallation, migratory insertion—have scarcely been studied in the case of gold or even remained unprecedented until recently. However, within the last few years, the ability of gold complexes to undergo these fundamental reactions has been unambiguously demonstrated, and the reactivity of gold complexes was shown to extend well beyond π-activation. In this Review, the main achievements described in this area are presented in a historical context. Particular emphasis is set on mechanistic studies and structure determination of key intermediates. The electronic and structural parameters delineating the reactivity of gold complexes are discussed, as well as the remaining challenges.

Sitting on a gold mine? In the past few years, the reactivity of gold complexes has been extended well beyond Lewis acid behavior and electrophilic activation of π-substrates. Elementary steps considered highly unlikely, if not impossible, for gold complexes have been unambiguously demonstrated, offering new perspectives in gold catalysis.

The mechanism of Stille reactions (cross-coupling of ArX with Ar′SnnBu₃) performed in the presence of fluoride ions is established. A triple role for fluoride ions is identified from kinetic data on the rate of the reactions of trans-[ArPdBr(PPh₃)₂] (Ar=Ph, p-(CN)C₆H₄) with Ar′SnBu₃ (Ar′=2-thiophenyl) in the presence of fluoride ions. Fluoride ions promote the rate-determining transmetallation by formation of trans-[ArPdF(PPh₃)₂], which reacts with Ar′SnBu₃ (Ar′=Ph, 2-thiophenyl) at room temperature, in contrast to trans-[ArPdBr(PPh₃)₂], which is unreactive. However, the concentration ratio [F⁻]/[Ar′SnBu₃] must not be too high, because of the formation of unreactive anionic stannate [Ar′Sn(F)Bu₃]⁻. This rationalises the two kinetically antagonistic roles exerted by the fluoride ions that are observed experimentally, and is found to be in agreement with the kinetic law. In addition, fluoride ions promote reductive elimination from trans-[ArPdAr′(PPh₃)₂] generated in the transmetallation step.

Fluoride does the job: Three roles for fluoride ions in Stille reactions are identified from kinetic data. F⁻ promotes the rate-determining transmetallation by formation of trans-[ArPdF(PPh₃)₂], which reacts with Ar′SnBu₃, in contrast to trans-[ArPdBr(PPh₃)₂], which does not. F⁻ also promotes the reductive elimination in trans-[ArPdAr′(PPh₃)₂]. However, the concentration ratio [F⁻]/[Ar′SnBu₃] must be less than 1 because of the formation of unreactive [Ar′Sn(F)Bu₃]⁻.

A novel Ni⁰-catalyzed carboxylation of aryl tosylates with carbon dioxide has been achieved under moderate temperatures and atmospheric pressure. In this procedure, the active Ni⁰ species is generated in situ by simply mixing the Ni⁰ precatalyst [NiBr₂(bipy)] with an excess of manganese metal. This approach requires neither a glove-box nor the tedious preparation of sophisticated intermediate organometallic derivatives. This mild, convenient, and user-friendly process is successfully applied to the valorization of carbon dioxide and the synthesis of versatile reactants with broad tolerance of substituents.

Direct carboxylation of aryl tosylates by CO₂ is rendered possible by a Ni⁰ catalyst, generated in situ by reduction of [NiBr₂(bipy)] with manganese metal. This approach, which requires neither a glove-box nor the preparation of a sensitive organometallic derivative, is applicable to a wide range of aromatic phenols, bearing either electron-donating or withdrawing substituents.

Catalytic enantioselective addition of organometallic nucleophiles to ketones is among the most straightforward approaches to the synthesis of chiral tertiary alcohols. The first such catalytic methodologies using the highly reactive organomagnesium reagents, which are the preferred organometallic reagents in terms of cost, availability, atom efficiency, and structural diversity, were developed only during the last five years. This Concept article highlights the fundamental breakthrough that made the development of methodologies for highly enantioselective Cu^I-catalyzed alkylation of ketones using organomagnesium reagents possible.

Catalytic enantioselective addition of organometallic nucleophiles to ketones is among the most straightforward approaches to the synthesis of chiral tertiary alcohols. This concept article highlights the fundamental breakthrough that made the development of methodologies for synthesis of tertiary alcohols via enantioselective Cu^I-catalyzed addition of organomagnesium reagents to ketones possible.

The asymmetric hydrocyanation of vinylarenes was investigated using hydrogen cyanide (HCN) in the presence of 5 mol% of a catalyst prepared from a phenol-derived chiral phosphine-phosphite ligand and bis(cyclooctadiene)nickel [Ni(cod)₂]. The reactions were performed in tetrahydrofuran (THF) at room temperature to give exclusively the branched nitriles with superior enantioselectivities of 88–99% ee for vinylarenes and 74–94% ee for vinylheteroarenes, respectively. Using styrene as a model substrate it was shown that the catalyst loading could be decreased to 0.42 mol% without any loss of selectivity (88% ee). The structure of the pre-catalyst, i.e., a tetrahedral Ni(0)(P,P-chelate)(cod) complex, was proven by X-ray and NMR analysis. Additional insight into the reaction course was gained by monitoring the hydrocyanation of styrene-d₈ by means of ²D NMR spectroscopy.

An unusual iron transfer and carbon–carbon coupling take place in gas-phase ionized mixtures containing ferrocene and dichloromethane. Ferrous chloride and the protonated benzenium ion are eventually formed by a thermal and efficient reaction, through stable intermediates that undergo a remarkable reorganization. The mechanism of the concerted iron extrusion, carbon–chlorine bond activation and carbon–carbon bond formation is elucidated by electronic structure calculations that show the crucial role of iron.

Ion–molecule reactions: A remarkable reorganization occured in iron-containing cations under ambient conditions. Fast and effective carbon–chlorine activation and carbon–carbon coupling was observed in gas-phase mixtures containing ferrocene and dichloromethane, through reaction intermediates (see picture) that eventually extrude the iron giving ferrous chloride.

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed CH olefination of unactivated aliphatic alkene to install the morphinan ring system.

Milk of the poppy: This paper reports a new strategy towards the synthesis of codeine and morphine, which features a cascade cyclization to construct the dihydrofuran ring and an intramolecular palladium-catalyzed CH olefination of an unactivated aliphatic alkene to install the morphinan ring system.

Radical changes: The applicability of alkene hydroamination has recently been significantly expanded by the development of radical variants that are based on initial hydrogen atom transfer to the alkene. This Highlight assesses the current state of the art, focusing on an iron-catalyzed reaction that utilizes stable nitroarenes as the electrophilic N component and is based on the dual catalytic activation of both starting materials.

A Pd-catalyzed direct cross-coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd-PEPPSI-IPr] or [Pd-PEPPSI-IPent] as catalyst allows for the efficient one-pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross-coupling is the use of an ortho-substituted bromide that undergoes lithium–halogen exchange preferentially.

Bro to Bro: A palladium-catalyzed direct cross-coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd-PEPPSI-IPr] or [Pd-PEPPSI-IPent] as catalyst allows for the efficient one-pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross-coupling is the use of an ortho-substituted bromide that undergoes lithium–halogen exchange preferentially.